A Novel Role for FERM Domain-Containing Protein 3 (FRMD3) in CKD.

Background: Currently there are limited methods to link disease severity and risk of disease progression in Chronic Kidney Disease (CKD). To better understand this potential relationship, we interrogated the renal transcriptomic profile of individuals with CKD with measures of CKD severity and identified FERM-domain containing protein 3 (FRMD3) as a candidate gene for follow-up study.

Methods: RNA-seq was used to profile the transcriptome of CKD biopsies from the North Dublin Renal BioBank the results of which were correlated with clinical parameters. The potential function of FRMD3 was explored by interrogating the FRMD3 interactome and assessing the impact of lentiviral mediated FRMD3 knock down on human renal proximal tubule epithelial cells by assessing cell viability, metabolic activity, and structural markers.

Results: We identified a subset of 93 genes which are significantly correlated with estimated glomerular filtration rate and percentage tubulointerstitial fibrosis at time of biopsy and with CKD progression 5 years post-biopsy. These results were validated against transcriptomic data from an external cohort of 432 nephrectomy samples. One of the top-ranking genes from this subset, FRMD3, has previously been associated with the risk of developing diabetic kidney disease. Interrogating the interactome of FRMD3 in tubule epithelial cells revealed interactions with cytoskeletal components of cell-cell junctions. Knockdown of FRMD3 expression in tubule epithelial cells resulted in increased pro-apoptotic activity within the cells as well as dysregulation of E-Cadherin.

Conclusions: We have identified a panel of kidney-specific transcripts correlated with severity and progression of kidney disease, and from this have identified a possible role for FRMD3 in tubule cell structure and health.